The Role of Insig-Mediated Cholesterol Homeostasis in Mouse Hair Development
Farooqi, Midhat Saleem
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Insig-1 and Insig-2, two very homologous proteins, are indispensable for feedback inhibition of cholesterol biosynthesis. Mice null for both Insigs drastically overproduce cholesterol and its precursor sterol intermediates and exhibit many developmental abnormalities such as cleft palate. In this work, we generate and characterize a line of mice lacking both Insigs in the hair and skin. These epidermal-specific, Insig-double knockout mice have many skin abnormalities, but their most striking defect is a complete lack of body hair. Epidermal-specific, Insig-double knockout mice also have a significant buildup of cholesterol precursors in skin, as they are unable to check endogenous cholesterol production. However, topical treatment of these mutant mice with simvastatin, an inhibitor of cholesterol biosynthesis, can reduce these sterol intermediates and completely correct the skin defects and alopecia. Further studies of epidermal-specific, Insig-double knockout mice showed that they had a dramatic decrease in the expression of many keratin-associated proteins relative to their control littermates. In the case of certain keratin-associated proteins, this loss of mRNA was especially severe; keratin-associated protein 28-13 expression, for example, was reduced by more than twenty-fold. Electron microscopy revealed that the hair shafts of mutant mice had grossly abnormal cuticles, and topical treatment of mutant mice with simvastatin rescued keratin-associated protein expression. We conclude that epidermal-specific, Insig-double knockout mice have a hair eruption defect due to improper formation of the hair shaft cuticle likely caused by a lack of keratin-associated protein expression. These findings are relevant to the multiple skin and hair abnormalities seen in human diseases where sterol precursors accumulate due to inborn errors in cholesterol biosynthesis.